A. Technical Field
The present invention relates generally to processes for synthesizing tertiary alkynols, in particular, 6,10,14-trimethyl-4-pentadecyn-6-ol compounds having the formula: ##STR2## wherein "R" represents H, or an alkyl group which can be aliphatic (e.g. tert-butyl), arylalkyl (e.g. benzyl) or part of a mixed acetal derivative ##STR3## These 6,10,14-trimethyl-4-pentadecyn-6-ol compounds can be readily converted to 3,7,11,15-tetramethyl-l-hexadecen-3-ol (isophytol), an intermediate used in both the manufacture of alpha-tocopherol (the most active Vitamin E factor known to occur in nature) as well as in the synthesis of Vitamin K.sub.1.
The 6,10,14-trimethyl-4-pentadecyn-6-ol compounds of the present invention can be prepared using the following novel alkylation reaction: ##STR4## R,R.sup.1 =alkyl and/or H and/or form part of an alicyclic ring (e.g., cyclohexanone).
R.sup.11 =an alkyl, alkenyl, aryl or arylalkyl group. PA1 (a) Section 302 (pages 218-220) in COMPENDIUM OF ORGANIC SYNTHETIC METHODS, VOLUME 2, edited by I. T. Harrison, et al. (John Wiley & Sons, Inc., 1974). PA1 (b) Section 302 (page 337) in COMPENDIUM OF ORGANIC SYNTHETIC METHODS, VOLUME 3, edited by L. S. Hegedus, et al. (John Wiley & Sons, Inc., 1977) . PA1 (c) T. W. G. Solomons, ORGANIC CHEMISTRY, Fifth Edition, page 471 (John Wiley & Sons, Inc., 1992). PA1 R.sup.11 =an alkyl, alkenyl, aryl or arylalkyl group. PA1 C. Reaction temperature: The reaction is complete in several hours if it is conducted at 20.degree. C. in a polar, aprotic solvent such as DMSO. Gentle heating (i.e., temperatures less than 100.degree. C.) can accelerate the reaction in less polar solvents. PA1 D. Side-reactions were minimal in virtually all systems examined. However, when a methyl ketone, i.e., ##STR13## was used as a reactant, it was necessary to add the methyl ketone slowly to the solution containing the terminal alkyne and the basic catalyst in order to avoid aldol condensations. PA1 E. Substrates: In addition to the preferred alkynediol (6) (whose synthesis is described infra), the following alkynols were prepared by the foregoing novel alkylation process using the reagents specified below: PA1 (b) excess acetone with a catalytic amount of aluminum isopropoxide; such conditions are used on an industrial scale in the manufacture of carotenoids. For some examples, see: PA1 (c) air, with a transition-metal catalyst. See: J. Chem. Soc. Chem. Commun., 157 (1977). PA1 (d) aqueous H.sub.2 O.sub.2 with a catalytic amount of WO.sub.4.sup.-2. See: J. Org. Chem., 51, 2662 (1986).
The process can also be used to synthesize tertiary alkynols in addition to 6,10,14-trimethyl-4-pentadecyn-6-ol derivatives.
B. Technical Background
The addition of an acetylide anion to a ketone to yield a 3.degree. alkynol is not a novel process per se; however, the conditions (i.e., catalytic amount of a relatively weak base) used in the present invention differ from those shown in the literature.
Numerous examples have been reported in the literature of transformations of the following type: ##STR5## However, all such examples (except for certain reactions involving acetylene, discussed below) teach that the use of one equivalent of strong base is required for a successful reaction. Specific examples can be found in the following references:
The commonly-held notion that one equivalent of a strong base is required for alkylation is not surprising in view of the known acidities of a terminal alkyne and representative alcohols. For example, Table 8.1 on pages 250-252 in ADVANCED ORGANIC CHEMISTRY: REACTIONS, MECHANISMS AND STRUCTURE, Fourth Edition, by J. March (John Wiley & Sons, Inc., 1992) lists the following pK.sub.a values:
R.sub.2 CHOH (a 2.degree. alcohol, as found in 4-pentyn-2-ol: 16.5 PA0 R.sub.3 COH (a 3.degree. alcohol ): 17 PA0 RCOCH.sub.2 R (an enolizable ketone): 19-20 PA0 HC.tbd.C--H: 25 PA0 NH.sub.3 : 38 PA0 CH.sub.3 CH.sub.2 --H : 50
Similar pK.sub.a values are listed in a widely-used organic chemistry textbook: T. W. G. Solomons, ORGANIC CHEMISTRY, FIFTH EDITION, Table 3.1 on page 94 (John Wiley & Sons, Inc., 1992). Such data indicate that strong bases such as NaNH.sub.2 or ethylmagnesium bromide can convert a terminal alkyne to an acetylide salt, which can subsequently be treated with a ketone to give a 3.degree. alkynol. On the other hand, alkoxides derived from 2.degree. and 3.degree. alcohols are expected to be too weakly basic to convert (appreciably) a terminal alkyne to an acetylide anion. Indeed, under the reaction conditions utilized in the present invention, one would instead predict conversion of an enolizable ketone to its enolate anion.
There are a number of patents, cited in R. J. Tedeschi, et al., J. Org. Chem., 28, 1740 (1963), that at first glance seem to suggest the alkynylation step of the present invention. These patents relate to the use of potassium hydroxide (comparable in basicity to an alkoxide) as a catalyst in the reaction of gaseous acetylene or vinylacetylene with aldehydes and ketones in liquid ammonia--a process referred to as the Favorskii reaction. However, a subsequent article by R. J. Tedeschi, J. Org. Chem., 30,. 3045 (1965), confirmed that the Favorskii conditions do not involve an acid-base reaction. Rather than involving the formation of an alkali metal acetylide, Tedeschi verifies the existence of an acetylene-alkalihydroxide complex in the Favorskii reaction.
In contrast, the alkynylation step of the present invention proceeds more rapidly with the strongest alkoxide bases: i.e., rates are greater when KOC(CH.sub.3).sub.3 is used rather than KOCH.sub.3, and reaction is even slower when powdered KOH is used as the basic catalyst. Moreover, unlike the Favorskii reaction, the process of the present invention proceeds poorly for several representative aldehydes, including isobutyraldehyde and benzaldehyde. Indeed, attempted use of the alkynylation process of the instant invention with benzaldehyde resulted in a significant amount of reduction of the latter compound to yield benzyl alcohol.
Attempts to alkylate 6,10-dimethyl-3,5,9-undecatrien-2-one (pseudoionone) using ##STR6## produced none of the expected 3.degree. alkynol, nor was any unreacted pseudoionone recovered. Since alpha, beta-unsaturated ketones such as pseudoionone are known to react with alkali-metal acetylides (generated by use of strong bases) to yield 3.degree. alkynols, the failure of the reaction when applied to pseudoionone was surprising. In contrast, the same alkylation using the related ketone, 6,10-dimethyl-2-undecanone, proceeded easily.
C. Utility of Products and Processes
F. G. Fischer and K. Lowenberg, Ann, 475, 183-204 (1929), have reported a synthesis of both isophytol and phytol utilizing the C-18 ketone (1) shown below as the key intermediate: ##STR7## Other syntheses of phytol have been reported in the literature, but they generally require lengthy sequences of reactions.
Treatment of either phytol or isophytol with the commercially available compound, trimethylhydroquinone, and an acid catalyst affords alpha-tocopherol, as outlined below: ##STR8## This synthesis is shown at pages 392-3 in Chemistry of Vitamin E, by O. Isler, et al., a chapter in VITAMINS AND HORMONES: ADVANCES IN RESEARCH AND APPLICATIONS, VOLUME 20, edited by R. S. Harris, et al. (Academic Press, 1962) .
Other processes for synthesizing vitamins E and K.sub.1 are illustrated in Chem. Abstracts, 67, 100,279z (1967); at pages 389-405 of VITAMINS AND HORMONES: ADVANCES IN RESEARCH AND APPLICATIONS, VOLUME 20, edited by R. S. Harris, et al. (Academic Press, 1962); in N. Cohen, et al., J. Am. Chem. Soc., 101, 6710 (1979); and in K. Chan, et al., J. Org. Chem., 43, 3435 (1978).